Randomized Controlled Trial of Genomically Directed Therapy in Patients With Triple Negative Breast Cancer

OUTLINE: This is a multi-center trial.

SEQUENCING:

DNA from archived tumor samples collected at the time of surgery (residual disease post neoadjuvant chemotherapy) will be extracted and sequenced. The resulting sequencing data will be interrogated for known genomic drivers of sensitivity or resistance to existing FDA approved agents.

CANCER GENOMICS TUMOR BOARD (CGTB):

Realizing that optimal treatment recommendations cannot be made based on sequencing data alone, the CGTB will be responsible for the final treatment recommendation. The CGTB will consider the genomic data along with the patient's prior treatment history, ongoing toxicities, and comorbidities. Preference will be given to the treatment identified by the sequencing data unless a significant clinical or safety contraindication exists for that therapy. All participants and investigators will be blinded to sequencing results and CGTB deliberations until the time of relapse.

PARTICIPANTS WITH A CGTB TREATMENT RECOMMENDATION:

Participants with a CGTB recommendation will be randomized to Experimental Arm A (genomically directed monotherapy) or Control Arm B (standard therapy).

EXPERIMENTAL ARM A (GENOMICALLY DIRECTED MONOTHERAPY):

Participants randomized to Experimental Arm A will receive an FDA approved drug at standard dose for four cycles (12-16 weeks total duration, depending on cycle length). Clinical and laboratory monitoring and dose-reductions will follow the FDA package insert guidelines.

TOP GENOMIC ACTIONABLE BIOMARKERS/PATHWAYS AND DRUG RECOMMENDATIONS:

• PIK3CA, PTEN: Everolimus
• TOP2A: Doxorubicin
• PARP1, BRCA1: Cisplatin and Olaparib
• VEGFA: Bevacizumab
• TYMP: Capecitabine
• SSTR2: Octreotide
• MGMT: Temozolomide
• MYC: Paclitaxel
• EGFR: Cetuximab
• COX2: Celecoxib
• hENT: Gemcitabine
• MET: Crizotinib

CONTROL ARM B (STANDARD THERAPY); Recently, a randomized phase III trial of over 900 HER2-negative patients demonstrated an improvement in disease-free survival (DFS) and overall survival (OS) for the addition of 8 cycles of capecitabine in the post-neoadjuvant setting. The hazard ratios were also significant in the triple negative subgroup. Thus, capecitabine can be considered a standard option in this setting. As this represents only a single trial (with prior data not demonstrating benefit for the addition of capecitabine in the neoadjuvant nor adjuvant settings in unselected patients), observation can be considered an option as directed by the treating physician. While not recommended, other therapies can be used as deemed appropriate by the treating physician.

In the event of disease progression on the control arm, patient sequencing results will be forwarded to the treating physician.

PARTICIPANTS WITH NO CGTB RECOMMENDATION:

Participants may have no CGTB recommendation either because 1) sequencing did not identify a matched drug or 2) the matched drug was contraindicated. These participants will be assigned to Control Arm B and treated as described above for Control Arm B. As the outcome of participants without an 'actionable' genomically directed therapy may differ, the primary analysis will include only participants randomized to Control Arm B.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days prior to study registration

Life Expectancy: Not Specified

Adequate laboratory values must be obtained within 14 days prior to study registration:

Hematopoietic:

• Hemoglobin (Hgb) ≥ 9.0 g/dL
• Platelets ≥ 100 K/mm3
• Absolute neutrophil count (ANC) ≥ 1.5 K/mm3

Hepatic:

• Bilirubin ≤ 1.5 x ULN (except in participants with documented Gilbert's disease, who must have a total bilirubin ≤ 3.0 mg/dL)
• Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN
• Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x ULN

Renal:

• Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula

Cardiac:

• Left ventricular ejection fraction within normal limits obtained within 30 days prior to study registration. NOTE: Participants with an unstable angina or myocardial infarction within 12 months of study registration are excluded.
• No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of the treating physician

Inclusion criteria

-Written informed consent and HIPAA authorization for release of personal health information.

NOTE: HIPAA authorization may be included in the informed consent or may be obtained separately.

NOTE: Central pathology review may be conducted any time after definitive surgery. Consenting participants may be pre-registered to the study and proceed with central pathology review before full eligibility has been confirmed. However, ALL of the eligibility criteria must be met and formal study registration completed prior to submission of the sample for sequencing.

• Age ≥ 18 years at the time of consent.
• ECOG Performance Status 0 or 1 within 14 days prior to study registration.
• Women and men of childbearing potential must be willing to use an effective method of contraception (e.g. hormonal or barrier method of birth control; abstinence) from the time consent is signed until 4 weeks after protocol therapy discontinuation.
• Women of childbearing potential must have a negative pregnancy test within 30 days prior to study registration. Women should be counseled regarding acceptable birth control methods to utilize from the time of screening to start of treatment. If prior to treatment after discussion with the subject it is felt by the treating physician there is a possibility the subject is pregnant a pregnancy test should be repeated.

NOTE: Women are considered not of childbearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they are postmenopausal for at least 12 consecutive months.

• Women must not be breastfeeding.
• Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer, clinical stage I-III at diagnosis (AJCC 6th edition) based on initial evaluation by physical examination and/or breast imaging prior to study registration. NOTE: ER, PR and HER2 status will be confirmed by central pathology review prior to randomization. ER and PR will be considered negative if ≤ 1% of cells stain weakly positive. HER2 will be considered negative if scored 0 or 1+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of < 2.0 or < 6 copies per cell.
• Must have completed preoperative (neoadjuvant) chemotherapy. NOTE: Acceptable preoperative regimens include an anthracycline or a taxane, or both. Participants who received preoperative therapy as part of a clinical trial may enroll. Participants may not have received adjuvant chemotherapy after surgery prior to randomization. Bisphosphonate use is allowed.
• Must have completed definitive resection of primary tumor. The most recent surgery for breast cancer must have been completed at least 14 days prior (but no more than 84 days prior) to study registration. NOTE: Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however participants with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy. Participants with margins positive for lobular carcinoma in situ (LCIS) are eligible. Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable.
• Must have significant residual invasive disease at the time of definitive surgery following preoperative chemotherapy. Significant residual disease is defined as at least one of the following:

• Residual Cancer Burden (RBC) classification II or III^6
• Residual invasive disease in the breast measuring at least 2 cm. The presence of DCIS without invasion does not qualify as residual disease in the breast.
• Residual invasive disease in the breast measuring at least 1cm with any lymph node involvement (does not include metastases in lymph node which are only detected by immunohistochemistry).
• Any lymph node involvement that results in 20% cellularity or greater regardless of primary tumor site involvement (includes no residual disease in the breast).
• Must have an FFPE tumor block with tumor cellularity of 20% or greater. NOTE: Prior to randomization, the tumor cellularity will be confirmed by central pathology review and percent values will be double checked at Paradigm (a Next Generation Sequencing Company).
• BREAST RADIOTHERAPY:

• Whole breast radiotherapy is required for participants who underwent breast-conserving therapy, including lumpectomy or partial mastectomy. Participants must have completed radiotherapy at least 14 days prior (but no more than 84 days prior) to study registration.
• Participants with a primary tumor > 5 cm or involvement of ≥4 lymph nodes who require a mastectomy must also have radiotherapy pre- or post-operatively at the discretion of the treating physician. For participants with primary tumors ≤ 5 cm or with < 4 involved lymph nodes, provision of post-mastectomy radiotherapy is at the discretion of the treating physician. Registration must occur within 84 days of the completion of the last local therapy.
• For radiation required prior to surgery, the participant must register within 84 days of surgery. Also, participants in this situation would not be required to have additional post-mastectomy radiation therapy.
• For those participants who do not require radiation, registration must be within 84 days of surgery.
• No stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.
• No treatment with any investigational agent within 30 days prior to study registration.
• No history of chronic hepatitis B or untreated hepatitis C.
• Adequate laboratory values must be obtained within 14 days prior to study registration.

• Hemoglobin (Hgb) >/= 9.0 g/dL
• Platelets >/= 100 K/mm^3
• Absolute neutrophile count (ANC) >/= 1.5 K/mm^3
• Calculated creatinine clearance of >/= 50 cc/min using the Cockcroft-Gault formula:

• Males: (140-Age in years) x Actual body weight in kg / 72 x Serum creatinine (mg/dL)
• Females: Estimated creatinine clearaNCE FOR MALES X 0.85
• Bilirubin </= 1.5 x ULN (except in participants with documented Gilbert's disease, who must have a total bilirubin </= 3.0 mg/dL)
• Aspartate aminotransferase (AST, SGOT) </= 2.5 x ULN
• Alanine aminotransferase (ALT, SGPT) </= 2.5 x ULN
• Left ventricular ejection fraction within normal limits obtained within 30 days prior to study registration.

NOTE: Participants with an unstable angina or myocardial infarction within 12 months of study registration are excluded.

• No clinically significant infections as judged by the treating physician.
• Must consent to allow submission of adequate archived tumor tissue sample from definitive surgery for genomic assessment of tumor.
• Must consent to collection of whole blood samples for genomic analysis
• No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of the treating physician.

Exclusion criteria

• No stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.
• No treatment with any investigational agent within 30 days prior to study registration.
• No history of chronic hepatitis B or or untreated hepatitis C.
• No clinically significant infections as judged by the treating physician.
• No active second malignancy (except non-melanomatous skin cancer or incidental prostate cancer found on cystectomy): Active second malignancy is defined as a current need for cancer therapy or a high possibility (> 30%) of recurrence during the study. Previous contralateral breast cancer is allowable unless it meets "active" criteria as stated above.